Study Update

Oct 22, 2018

Press Release

Good afternoon, and welcome to Kura Oncology's ESMO conference call. Joining me on the call today is Doctor. Troy Wilson, our President and Chief Executive Officer Doctor. Antonio Alberto, our Chief Medical Officer and Head of Development and Doctor. Mark Grasso, our Chief Financial Officer and Chief Business Officer, are also on the phone with us and available to answer your questions during the Q and A portion of the call. Before I turn the call over to Troy, I would like to remind you today's call will include forward looking statements based on current expectations. Such statements represent management's judgment as of today and may involve risks and uncertainties that could cause actual results to differ materially from expected results. Please refer to Kura's filings with the SEC, which are available from the SEC or on the KURA Oncology website for information concerning risk factors that could affect the company. With that, I will now turn the call over to Troy Wills. Thank you, John, and thank you all for your patience. We had some audiovisual issues. Earlier today, we reported an update on our positive Phase 2 study of Tipifarnib in HRAS mutant head and neck squamous cell carcinomas and preliminary results in other HRAS mutant squamous cell carcinomas. The update was presented by Doctor. Alan Ho of Memorial Sloan Kettering Cancer Center and Principal Investigator of the study at the European Society For Medical Oncology 2018 Congress here in Munich. A copy of Doctor. Ho's presentation is available on our website. I encourage you to pull it up if possible as I'll be referencing it during the call. You'll also find a copy of our updated corporate presentation there on our website. To our knowledge, Tipifarnib is the 1st small molecule inhibitor of a RAS oncogene in clinical development. We are encouraged that tipifarnib continues to show meaningful clinical activity, including objective responses in difficult to treat squamous cell carcinoma. As pioneers in the development of farnesyltransferase inhibitors as precision medicines, we are committed to advancing the science of how they can best be used in patients. In this regard, we're very encouraged by our novel observation of a significant association between tumor HRAS mutant allele frequency, a tumor's ratio of HRAS mutant to wild type and clinical benefit in our Phase 2 study. We believe this association is meaningful because although current next generation sequencing technologies can detect mutations lower than 1% allele frequency, we have observed that an allele frequency of at least 20% appears to be associated with objective responses in HNSCC or SCC patients with Tipifarnib. Our data as well as data from the Cancer Genome Atlas or TCGA indicate that depending on the allele frequency of HRAS mutation, the percentage of HRAS mutant patients is between 5% 8% of HNSCC in Western patients. Higher rates have been reported in Asian patients. We intend to incorporate the learnings related to allele frequency into the planned AIM HN registration directed study, which remains on track to initiate later this year. In addition, based upon our evaluation of doses ranging from 600 to 900 milligrams twice daily in the Phase 2 study, we have determined that our upcoming registration directed trial will proceed with a starting dose of 600 milligrams twice daily administered orally. Now let me quickly recap the presentation by Doctor. Ho, who provided data from 2 cohorts of patients. The first is a cohort of 17 patients with HRAS mutant HNSCC. The second is a cohort of 6 patients with other HRAS mutant SCC. The data cut off for both cohorts was September 7, 2018. In the HRAS mutant HNSCC cohort, tumor size reductions were observed in 9 patients with 5 confirmed PRs as of the data cutoff, including 3 patients with durable response lasting more than 17 months. A 6th patient achieved a confirmed PR after the data cutoff. Four patients had stable disease, including 2 who experienced prolonged disease stabilization greater than 6 months. This is summarized by the swim lanes on Slide number 7 of Doctor. Ho's presentation. 6 of the 17 patients were not evaluable as of the data cutoff date, including 3 early deaths related to disease under study, 2 consent withdrawals and one pending an initial efficacy assessment. In addition, we're monitoring the progress of 1 additional HNSCC patient dosed off protocol who has an unconfirmed PR. The patient experienced a 40% tumor size reduction at first assessment and is continuing to receive treatment. The cohort of other hRAS mutant squamous cell carcinomas enrolled a total of 6 patients. 1 of the 2 evaluable patients in this cohort achieved a confirmed PR, 4 patients were not available as of the data cutoff date, including 2 patients who were pending initial efficacy assessment. Although diagnostic technologies have advanced to the point where tumor HRAS mutant allele frequencies lower than 1% can be detected, the relationship between allele frequency and clinical benefit with tipifarnib had not yet been identified when we started this trial. After extensive characterization of the genetic makeup of squamous cell carcinomas from 20 patients, we have observed that such an association exists. If you were to turn to Slide 11 of Doctor. Ho's presentation, you would see that of the 13 HNSCC or SCC patients with a tumor HRAS mutant allele frequency greater than 20%, 6 achieved PRs, 1 achieved an unconfirmed PR and 2 experienced disease stabilization greater than 6 months. In other words, meaningful clinical benefit in 9 of 13 patients. In contrast, no meaningful clinical benefit was observed in the 7 patients with an allele frequency less than 20%. We believe these findings give us insight into which patients are most likely to benefit from tipifarnib, namely those with allele frequencies greater than 20%. We're currently investigating how tipifarnib may also address the unmet medical need of those patients with allele frequencies lower than 20%. We want to stress that although we're still finalizing the precise allele frequency cutoff for use in the future, the significance of the association seems clear. The next logical question is whether we lose patients by establishing an allele cutoff. Our internal data indicates that approximately 8% of HNSCC patients have a tumor HRAS mutant allele frequency greater than 1% and 5% of HNSCC patients have an allele frequency greater than 20%. A second takeaway from the Phase 2 data presented by Doctor. Ho is that we now have a better understanding of the starting dose. Our goal with each of our Phase 2 trials is to establish a dose and schedule that will maximize the opportunity for patients to receive clinical benefit while providing acceptable tolerability. Patients have been receiving oral doses ranging from 600 to 900 milligrams in the ongoing Phase 2 trial. Although our early experience with HRAS mutant patients treated at major medical centers suggested that 900 milligrams might be the optimal regimen, we have determined that 600 milligrams twice daily to be the recommended dose as we expand into more clinical sites around the world. As shown in the ESMO presentation, 4 of the responses and 2 disease stabilizations greater than 6 months were observed while on treatment with 600 milligrams twice daily dose, indicating that dose is sufficient to drive clinical activity. Moreover, given that Tipifarnib is a targeted therapy, our goal is to provide maximum clinical benefit in a selected population. By selecting patients with tumors with increased sensitivity to tipifarnib, we believe we can achieve a higher therapeutic index in the clinic. For these reasons, we intend to introduce a starting dose of 600 milligrams twice daily along with a minimum HRAS mutant allele frequency anticipated to be no lower than 20% as an entry criteria in our upcoming AIM HN study. In closing, it's worth emphasizing again that we're breaking new ground with tipifarnib. Although the HRAS oncogene was discovered more than 40 years ago, it has resisted all efforts at developing an effective therapeutic. We're encouraged by the progress reported today at ESMO. In particular, we believe the identification of a significant association between tumor, mutant allele frequency and objective response in our Phase 2 trial is a meaningful advance for the field. Moreover, by coupling the allele frequency with our recommended dose in the pivotal, we're excited to start our upcoming registration directed trial, which remains on track to initiate by year end. With that, operator, we're now ready for questions. Thank And our first question comes from Jonathan Chang of Leerink Partners. Your line is now open. Hi, guys. Thanks for taking my questions. First question, can you provide more color on the non evaluable patients for both the head and neck and other squamous tumor types? Jonathan, we're having a really hard time hearing you. Can you get closer to the phone or speak up? Yes, sure. I'm wondering if you can provide more color on the non evaluable patients for both the head and neck and other squamous tumor types? Sure. Let me let Antonio answer the question about more color on the not evaluable patients. Yes. There were 3 patients that the best way to put it that they were fairly sick patients. So these are patients that may have joined the study, received Tipifarnib for a few days, maybe have an adverse event and have to be hospitalized. The moment you stop treatment in those patients, those patients, they undergo symptomatic deterioration, they may die on a study. The conclusion for those patients initially was that simply they are too sick patients to be on a study. As you can see later, what we discovered that those patients have very low allele frequency of their RAS mutations. So the initial interpretation is they are too sick for a study. Then we saw patients that are also fairly sick. They have poor performance status, but responded. So our conclusion then is those that are missing this driver of the higher allele FAS mutations are those that once they discontinue treatment, they suffer symptomatic deterioration. There were also a couple of patients that they have consent withdrawal and these are a couple of patients that they actually have to travel from the initial hospital to the treatment center. That we are not seeing clinical benefit. They have some minor adverse events, but they decided to discontinue the trial. And then we have in the squamous setting, there are 2 patients that initially some creatinine elevations. I mean those patients who have been hydrated, but they decided to discontinue the trial. At the end of the day, all those patients are patients that do appear to have very low allele frequency of FESTRAS and biologically they don't right now we know there wouldn't be an expectation of clinical benefit. Great. Thank you. That's helpful. Second question, can you talk about reasons for confidence in the 600 mg BID dose? How much of a risk is there in potentially sacrificing efficacy? Yes. Actually, I do believe that the 900 milligrams is actually a higher risk. And the reason is that if you're trying to give a high dose and then the patient developed adverse events, then the patient had to undergo dose reduction, dose discontinuation. So at the end of the day, if you give a high dose, but you have discontinuations as a median, you finish giving 600 milligrams or lower. So it's a better idea to give a dose that is better tolerated, a dose that you can maintain for a longer period of time and at the end you get better dose intensity. So we have seen, as you may have seen in the presentation of Doctor. Ho, a patient that due to frailty started with 600 milligram, we gave a waiver of protocol to that particular patient because we may not be able to tolerate high doses. That patient moved very quickly to a partial response. There were 3 additional patients that started with 900, but they had to be dose reduced. At the end of the day, they continue with the 600 milligram dose and they undergo a Paltra response with that dose and 2 additional patients that also were dose reduced to 600 very early in the study and they finished having this prolonged disease stabilization more than 6 months. Got it. Thank you. And just one last one. Broadly, can you talk about the reasons for confidence that Tippie could address other squamous tumor types beyond head and neck and talk about your overall strategy there? Thank you. Sure, Jonathan. So the data that gives us confidence that tipifarnib could address other HRAS mutant squamous cell carcinomas is a combination of sort of genomic data, preclinical data and now some early clinical data. So at our Investor R and D Day late last year, Antonio showed the sort of genomic landscape not only of head and neck squamous cell carcinomas, but also of 2 other squamous cell carcinomas. And you see at a qualitative level, a lot of similarities, very little other genetic dysregulation and situations where HRAS is truly the driver. We've also observed in our preclinical models and patient derived xenografts that we can drive tumor regressions with tipifarnib. And then most recently, we were encouraged, it's very early data, it's preliminary, but of the 6 patients with other SCCs to see one patient with cutaneous squamous cell carcinoma who had prolonged disease stabilization and now a second patient with penile squamous cell carcinoma that has a confirmed partial response that gives us confidence. We will be implementing the same changes in terms of both the dosing schedule and setting a cutoff for allele frequencies in each of our HRAS mutant Phase 2 studies as well as as we indicated in the pivotal trial. And what I think what we're excited about is that we can we've now identified that the real responders represent that population that is 20% or greater in allele frequency and that's about 5% of HNSCC. If you want to go below that, there may be other ways to treat those patients that could enlarge the population to, as I indicated, 8%. We're still running the numbers and learning more about the epidemiology of the other squamous cell carcinomas. And hopefully, we'll be able to provide some updates at some point in the future on that. Great. Thank you. Thank you. And our next question comes from Joel Beatty of Citi. Your line is now open. Hi. Thanks for taking the questions. The first one is on the dose reductions in to 600 milligrams in a few patients that had responses. Could you discuss the timing of that and how early in treatment that happened? Yes, that happened very soon. So there are some patients that do appear to tolerate 900 milligrams. They have to stay long time in a study. But as we were expanding the study to other sites, other countries, other standard of care, patients that have higher degree of tumor burden, we noticed that on other comorbidities, we noticed that some patients from the get go by cycle 1, they had to be dose reduced to 600 milligrams. Despite that, the patients that have the higher allele frequency, they do well with the 600 milligrams. They do well even if or even if they have bad performance. So that basically we're demonstrating is that SRAS is a driver of the tumor and you can see clinical benefit even with the dose of 600 milligrams. Got it. And then another question is on Slide 11 showing the benefit by allele frequency. It looks like there's 4 patients on the chart that still have allele frequency data pending. Could you discuss the reasons for that and if there's potential to get that data in the future? Yes. It's simply, I mean, one of the patients is in South Korea and other patients is in France. Some of the samples just take longer than others. The samples, they just need to be processed QC before we do the analysis. Obviously, we were very pressured to generate these data for ESMO, but we will eventually will obtain those samples as well as any samples for additional patients coming to the study. Yes, Joel. 1 of the patients that's not represented on Slide 11 is the Paris patient with a very dramatic resolution of the facial lesions that's in our corporate presentation. And then as Antonio mentioned, there are 3 other patients as well. We don't expect that that's going to meaningfully change our conclusion that the cutoff will be no less than 20% of allele frequency. We think with this data set 20 out of 24 patients, that probably gives us sufficient confidence to be able to move forward. But as Antonio mentioned, if and when the additional data or additional allele frequencies come in, we'll obviously take that into account. Got it. And if I could ask one last question. On the what's it learned over time on the prevalence of HRAS patients in head and neck cancer? I believe at the R and D Day from over a year ago now, it was estimated at roughly 5% of all head and neck squamous cell cancer patients have HRAS mutant and now it appears that it's roughly 5% with the allele frequency above 20% or so. So could you discuss what's been learned on EPIGRID? Yes. We are simply learning. So initially, when we look at the database, for example, if you look at TCJA, head and neck provisional, you see a number like 6%. So whether that's the number 6%. If you go then to the individual tumors, you will notice that they have a cutoff of 10%. So they have only counted tumors that have 10% allele frequency and higher, probably because that was the limit of the patient at the time that, that risk was created. Something that we have been doing in the last 2 years is creating more sensitive assays. And they say that we currently work with half a limit of the patient of around 1% for tumor biopsies. And that's the cutoff that was used to enroll many of these patients. That is what we correspond to 8% of the population. Now that is an analytical cutoff, and this type of exploratory study needs to be done. So you can identify a clinical cutoff. And basically, that's the analysis that we have done here. We internally we talk about the sample of And then clinically, you determine that you can only dose the HER2, HER2 and HER3 plus So similar exercise. And our next question comes from Joe Pantginis of H. C. Wainwright. Your line is now open. Hi, guys. Thanks for taking the question. First, I just want to make an observation. It's really intriguing. I don't know if you wanted to comment about the rapidity of the responses that you're seeing with tipifarnib. I don't know if you can maybe add some commentary to these kinetics. Yes, Joe, thanks for the question. If we focus on the patients with the allele frequencies greater than 20%, we pretty consistently see rapid and in some cases pretty dramatic responses. As we've gotten more experience, we've seen responses as early as cycle 2. In some cases, we see tumor shrinkage, but not quite a response until cycle 4. But they do appear when the tumor is sufficiently enriched in HRAS mutations that you get rapid responses. And that's because the AIM HN pivotal trial, because the goal there is to have at least 15 objective responses out of at least 59 patients. Obviously, as Antonio mentioned, we're learning, we're doing everything we can to maximize the therapeutic index and to be able to provide the best outcome of objective response in that trial. And that's what has us excited about this latest update. We're learning. This is the 1st drug to treat RAS, so you learn as you go. But I think this is, as we said in the prepared remarks, a pretty significant advance for the field in terms of this association around HRAS mutant tumor allele frequency. Let me just add, I do believe that when HRAS is a driver, you start seeing reductions the moment you start the treatment. What happened is that the scans are scheduled at certain times just from clinical practice. So in many cases, you do the investigator that is kind of cycle 2 and it is 35%, so we call it EPR. But in other cases, one of the cases, for example, have a 28.7% reduction. So we cannot call it EPI, PR, but it's in their way to become a partial response. So many of these patients, even if the response happening at cycle 4, already have 20%, 25%, 28% tumor side reduction by cycle 2. That is the first one on the study ASCOM. Got it. No, that's helpful. Thank you. And first, if I could also ask a logistical question. Can you just describe the off protocol patient? Was it enrollment criteria based? Or what were the factors? This is just kind of like regulatory procedure. So we are now in Germany, so we have a number of German investigators that are quite interested in participating in our study. So as you can imagine, we have to go through the regulatory procedure, open sites, etcetera. So this is a patient that was identified by the site in Boukur, and they were quite interested. And unfortunately, the patients were progressing very quickly. So it was not going to we were not going to have enough time to open the clinical site on time. So we initiated compactionate use. It's actually it's a very easy procedure. In Germany, probably easier than in the states with the purpose to initiate treatment as soon as possible and then roll the patient into the study. Got it. And then my last question, if you don't mind, thank you, is with regard to now adapting the protocol for the current Phase II and the upcoming AIM study, what sort of regulatory interactions have you had yet? Or when are they planned for this to change the protocol? Thanks. So we wouldn't need regulatory interactions in the 600 milligram doses have been already incorporated in the pivotal and the cutoff of the allele frequency is just a laboratory procedure. So this is more of a question of laboratory manual. So basically, there's nothing that will signify a delay or we need to further discussion with the agency. Understood. Thanks guys. Thanks, Joe. Thank you. And our next question comes from Pam Barrant of Cowen. Your line is now open. Hi, guys. This is Pam Barrant on for Chris Shibutani. I guess my first question is, was there anything inherently different about the last several evaluable patients that you evaluated compared with the first six that were presented in February? I mean, the major difference, Pam, is we've been pushing the limit in terms of our ability to detect HRAS mutations. And the diagnostic is now able to detect HRAS mutant allele frequencies down to 1%. We continue to innovate in the areas of diagnostics. Out of that, as Antonio mentioned, when we got a handful of patients that were coming off the study, the first thought is, well, maybe the patients are too sick to be on study. But then when you go in and you actually look at the allele frequency, it's compounded by the fact that they don't have a sufficiently high allele frequency really to be treated with tipi as a monotherapy. So I don't think it's so much a focus on the evaluable patients as on how do we define that subset of patients where we can maximize the therapeutic index and select those patients who have the greatest likelihood of either a partial response or prolonged disease stabilization. And that's the significance of this cut off. And it just it took us an additional sort of 10 patients or so to figure it out. The good news is we figured it out. We're in the process of implementing all those changes. The timelines are unchanged from the guidance we gave earlier. But I think we're optimistic and looking forward now to not only executing on the pivotal trial with these changes, but now rolling this back through the ongoing Phase II trials. And then we never give up. So we are looking for other ways of treating the low allele frequency patients as well. But that's more work to be done there. Got it. That's very helpful. So initially, we thought kind of like the usual suspects. So you go to other countries, there's other standard of care. Some of the patients, they have to displace from one place to another. 1 of these patients, for example, is in Southern Spain, had to go all the way to Barcelona to get treated. So we thought maybe we're just getting more sicker patients. But then the reality at the end of there's also the antithesis, not that we are getting very sick patients in other settings and they translate to responses. So that's what we move us to say, it must be a biological question. So that's what the reason to proceed with the analysis of allele frequency and that actually is what they're providing the answers. Irrespective of the performance status, the tumor burden, if the tumor has high allele frequency is translated to responses. So that's the best explanation that we have. Great. And if I can ask one follow-up. Is there a reason to think that the null hypothesis or the 30% ORR you were going for as a minimum in the pivotal study, is there a reason to think either of those would change? I believe your null hypothesis was 15%. Is there a reason to believe those would change with the dosing or with the 20% cutoff for the allele frequency? No, they shouldn't change, Pam, because the 15% null is based off the point estimate of second line therapy, right? So and that's in the all comers population. We know you don't see PRs in this population typically with other therapies or at least with the currently approved therapies. So it shouldn't change that. It does give us greater confidence, because the better you can define your eligible patient population, the more likely you are to have a positive trial. And that's what we think. The combination, as Antonio mentioned, of we now know the patients for whom we can drive objective responses are 20% allele frequency or greater and we can drive it at 600 milligrams twice daily on alternating weeks, which gives us the maximum therapeutic index. This is the precision nature of precision medicine, is combining the drug and the way you use it with the right population. And so that has us encouraged with the pivotal and we're very happy that we've taken the few months that it's taken to learn, as Antonio mentioned, about the biology and make these important changes. So let me just mention. So in any case, the fact that we have now a potential clinically relevant cutoff for the allele frequency, it only can influence how potentially transformative the outcome of the study could be. So we know that remember that our study, our pivotal study has a treatment cohort and then we have an observational cohort. And that observational cohort is going to help us to understand how a patient that carry SRAX mutation is going to respond to the standard of care. Now that we have potentially a higher cutoff, you are expecting the patients in the observational arm to potentially do worse. So 20% allele frequency increase the possibility of response to tifafarnib, but we also expect that most likely will decrease the probability of the patient to respond to the standard of care. So now instead of seeing 15% for the standard of care, we are seeing 2% for the standard of care and we are having, let's say, a 30%, 40%, 50% response rate in our trial. That will be a therapy that will be transformative for that setting because you are not seeing any meaningful benefit with the current standard of care for those patients. Thank you. And that concludes our question and answer session for today. I'd like to turn the conference back over to Troy Wilson for closing remarks. Thank you all once again for taking the time to join the call. We'll be hosting our 3rd quarter conference call in about 2 weeks, and we look forward to speaking with you again then. In the meantime, if you have any additional questions, please feel free to contact Pizza Spain, Mark Grasso or me. Thank you again and have a good day everyone. Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program and you may all disconnect. Everyone have a great day.